Age-related macular degeneration (AMD) causes severe, irreversible vision loss and is the leading cause of blindness in individuals older than 50 years in the Western World. The Framingham study reported the prevalence of AMD in the United States as 1.2% of the population between 52 and 64 years of age, with an increase to 20% in patients over the age of 75. The Beaver Dam Eye Study reported an incidence of 37% in patients 75 years and older. Most patients have the non-neovascular (“dry”) form, characterized by drusen and atrophic changes in the retinal pigment epithelium (RPE). Eighty to ninety percent of the severe vision loss due to AMD, however, is attributable to the form characterized by choroidal neovascularization (CNV), also called “wet” AMD. CNV is an ingrowth of choroidal capillaries through a break in the outer aspects of Bruch's membrane. In the United States, between 70,000-200,000 individuals over the age of 65 develop the wet form of AMD every year. Slightly lower estimates of prevalence and incidence of CNV secondary to AMD have been reported in the Netherlands but higher estimates have been found in England. The great majority of wet AMD occurs subfoveally.
CNV in wet AMD can be generally divided into two classes, “classic” CNV” and “occult” CNV. The two forms are distinguishable by angiography conducted with fluorescein dye. Classic CNV is generally defined by a well-demarcated area of bright hyperfluorescence throughout the transit phase of the angiogram with leakage in the mid and late phase frames. Vessels of the neovascular lesion often will be visualized in the early phase of the angiogram, but are not required to be identified. Occult CNV includes fibrovascular pigment epithelial detachment (a type of occult choroidal neovascularization in which areas of irregular elevation of the retinal pigment epithelium are detectable on stereoscopic angiography and consists of an area of stippled hyperfluorescence noted within 1 to 2 minutes after fluorescein injection). Persistence of fluorescein staining or leakage within this area occurs within 10 minutes after fluorescein injection. These areas are not as discrete or bright as areas of classic choroidal neovascularization or serious detachment of the retinal pigment epithelium in the early phase of the angiogram. In addition, occult CNV may show late leakage of an undetermined source (a type of occult choroidal neovascularization in which areas of leakage at the level of the retinal pigment epitherim in the late phase of the angiogram are without well-demarcated areas of hyperfluorescence from classic CNV or a fibrovascular pigment epithelial detachment discernible in the early phase of the angiogram that account for the leakage.) A detailed description of classic and occult CNV lesions appears in Arch. Ophthalmol. 1991; 109: 1242-1257. Although no formal studies are available on the prevalence of lesion subtypes, it is estimated that patients with occult lesions represent 60-80% of all patients who present with subfoveal neovascular AMD.
A CNV lesion can be comprised only of occult CNV, which is termed occult CNV with no classic CNV. Some lesions comprise both classic and occult CNV. A lesion in which the area of classic CNV occupies more than 0%, but less than 50% is termed “minimally classic”. A lesion in which the area of classic CNV occupies at least 50% of the area of the entire lesion is termed “predominantly classic.”
In CNV, the newly formed vessels have a tendency to leak blood and fluid, causing symptoms of scotoma and metamorphopsia. The new vessels are accompanied by proliferation of fibrous tissue. This complex of new vessels and fibrous tissue can destroy photoreceptors within 3 to 24 months. At the same time that existing CNV is destroying retinal tissue where it has formed, the lesion can continue to grow throughout the macula, resulting in progressive, severe and irreversible vision loss. Without treatment, most affected eyes will have poor central vision (<20/200) within 2 years. In addition, when one eye of an individual develops CNV, the fellow eye has about a 50% chance of developing a similar CNV lesion within 5 years.
At present, there are no proven treatment options for CNV characterized by occult with no classic lesions, or minimally classic lesions. Laser photocoagulation is limited to selected cases because the treatment destroys any viable photoreceptors overlying the area affected by CNV, often resulting in immediate visual acuity loss, especially when the lesion is subfoveal and the visual acuity is 20/200 or better. For this reason, laser photocoagulation is only indicated for well-demarcated extrafoveal and juxtafoveal CNV lesions as well as small, well-demarcated subfoveal lesions that have a pattern of classic CNV on fluorescein angiography. Recurrences following standard laser treatment of AMD cases occur in approximately 50% of cases. The recurrent CNV can lead to further vision loss, especially when the originally treated lesion was extrafoveal or juxtafoveal.
Photodynamic therapy (PDT) with verteporfin (VISUDYNE™, Novartis Ophthalmics) offers an approach to selectively destroy CNV without significant destruction of overlying retina tissue, possibly by occluding the new vessels within the CNV lesion. Photodynamic therapy is a two-step process consisting of an intravenous injection of a photosensitizer (light-activated drug) followed by light application. The light sources most commonly used are non-thermal lasers or light emitting diodes (LEDs). Verteporfin preferentially accumulates in neovascular tissues, including the endothelial cells of choroidal neovascularization. In combination with localized light administration, this allows for selective treatment of the pathologic tissue. After exposure to light at a wavelength of 689 nm, an energy transfer cascade is initiated, culminating in the formation of singlet oxygen which generates intracellular free radicals. These free radicals can disrupt cellular structures such as the cell membrane, mitochondria, and lysosomal membranes.
Occlusion of the neovasculature is presumed to be the major mechanism of PDT with verteporfin. Occlusion can occur through free radical damage to the endothelial cells, causing subsequent platelet adhesion and degranulation, and thrombus formation. A reduction in blood flow from the new vessels may lead to a confinement in the growth of the fibrovascular CNV lesion with subsequent reduced risk of further vision loss compared with no treatment. Thus, verteporfin PDT reduces the area of the macula affected by CNV and spares viable photoreceptors from destruction caused by fibrovascular disorganization of the outer retina.
Photodynamic therapy of neovascular conditions in the eye has been attempted over the past several years using a variety of photosensitive compounds, e.g. porphyrin derivatives, such as hematoporphyrin derivative and porfimer sodium (PHOTOFRIN® Axcan Pharmaceuticals), phthalocyanines, green porphyrins (such as verteporfin, also known as BPD-MA), purpurins, such as tin ethyl etiopurpurin and texaphyrins, such as motexafin lutetium. The photosensitive compound verteporfin (Visudyne™, Novartis Ophthalmics) is the only photosensitive compound to have received regulatory approval (from the U.S. Food and Drug Administration (FDA) and corresponding agencies approximately 30 other countries) for the treatment of CNV, but has only proven its efficacy in clinical trials in the predominantly classic form of the disease (see Arch. Ophthalmol. 1999; 117: 1329-1345) Hence, there is still no approved PDT treatment for AMD patients having predominantly occult, rather than classic, lesions.
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